Steroid pyridinium salts



Patented Jan. 5, i954 UNITED STATES QFFICE.

2,665,274 s'mnom PY-RIDINIUM sAL'rs,

John P. Qonbere; Plainfield, N. .L, assignor to: Merck &-Co., 1110.,Rahway, N. J.,,a corporation oiFNewlerseY" No Drawing. Application April30,1952,

Serial No. 285;;329-

13 Claims. (Cl. 260-2395); 1 2

This invention relates to;nov el quaternary amd-mcortisone-withpyridinein' the: presence=of an monium salts ofcyclopentanopQlyhydrophenaromatiosulfonyl halide; This reaction-maybeanthrene compounds and processes of. obtaining showmasifollowsz thesame; more particularly, it is concerned with OH OH new pyridinium saltsderived-from cortisone, (A 5 117a,21-dihydroxy;-3,l1,20-triketopregnene) and =0 hydrocortisone, (M-l13,1'7a,21-trihydroxy 3,20-- diketopregnene) and methods for thepreparation of these salts.

Cortisone and hydrooortisone; and in' particular I.

the ZI-acetoxy derivatives thereof; have been A u] found to beg-veryeiiective in the treatment of 5 m f rheumatoid arthritis,

The new quaternary: ammonium salts derived from cortisone andhydrocortisone, which may be 7 represented as follows: OHPNO whe niR' re ts-a keto or hr gr u wherein R isaa keto or hydroxy group and X is anendl wrenr sents ananion from the group conT anion from the groupconsistin of halide and SiStiI'lg Of halides and aromatic sulfonicacidjradi: aromatic sulfonic acid radicals, are. useful as in- 0915- te-mediates in the preparation of other no el This reaction iSconveniently efieoted by discompounds having com-5911641116 activity.For solving cortisone or'hyd-rocortisone' inpyridineexample, disclosedin copending, application and adding theretoianz aromatiesulfonyl halideSerial No. 285,318, filed April 30, 1952, these na abe ner u fonylchloride, naphthalene pyridinium salts may be utilized in the preparallfbny bliomldentoluene ul en o d vtolution of A-l'laehydroxy-3,11,20-triketo21-pregneene-s l n l bromide, benzene sulon l bromide, nal and Nell/351,711?dihydroxyfififivdiketo-21- eRh eleneu ffln l. chle e and. the like). pregnenal.

111s esult g e ion mixt reiisst e permi ted It is an object ofthespresent invention torpro- 4 te sianda lniempe ati eorsiiiiieienttime vide novel 2il-pyridiniu 'n salts "derived from cor- 9mp etaihe e ion T:h ti0n-,results.in tisone and hydrocortisone, Anotherobject ;is to 1 lm n o -emi th zkpyridinium provide processes for thepreparation of these ali le a fllld p i l h e salts from cortisoneandhydrocortisone. Other Q -Qi QIl d hydrocorti sone. objects will beapparent frornthe detailed desorip- Thusnpul'suam 170-94 i v mb dimentof this tion hereinafter provided. Procedure p-toluenesulfonrl h d ybeIte- In accordance with my presentinvention, it is W -01 S ne in pyidine. at roomtemperanow found that these valuable pyridinium detumlntil-com 1 t nv of thereaction; Therea'c rivatives of cortisone andhydrocortisone ares-con- 5o al fiultss-in the: formati Qi a;-,m1-Xt1l1r3()f veniently prepared by reacting ;cortisone'-or hy- 17a-=-hy,drn 3,'1l,20K--triketop -en nil ,tg fl pyridinium p-toluenesulfonate and A -17a-hydroxy 3,11,20 triketopregnenyl 21 pyridiniumchloride. The 21-pyridinium chloride derivative may be obtained from thereaction mixture by separating the solid formed and washing withacetone. By concentrating the reaction mixture to dryness under reducedpressure, triturating the residue with acetone, and filtering ofi thesolid a mixture of the 21-pyridinium p-toluenesulfonate and21-pyridinium chloride derivatives of cortisone is obtained from whichthe 21-pyridinium ptoluenesulfonate derivative is obtained by fractionalcrystallization from a suitable solvent such as methanol or ethanol.

The following examples are presented as illustrative embodiments of myinvention:

EXAMPLE 1 pregnen'yZ-ZI -;yridinium p-tolz enesuifonate Cortisone (3.6g.) was reacted with p-toluenesulfonyl chloride (2.4 g.) in pyridine (50ml.) and allowed to stand in the dark for 12 days.

The reaction mixture was pumped to dryness and 30 ml. of acetone wasadded to the residue. After standing overnight the solid was recoveredby filtration and dissolved in methanol, treated with charcoal, dilutedwith 100 ml. of 95% ethanol and concentrated to 70 ml., cooled, thecrystals collected and air dried to give 3.3 g. of product, M. P.285-290 C. (d.).

Calc. for C33H3907NSZ C," 66.75; H, 6.67. Found: C, 66.58; H, 6.70.

The 21-pyridinium-p-toluenesulfonate derivative of hydrocortisone (A-11c,17a-dihydroxy- 3,20-diketopregnenyl-2l-pyridinium ptoluenesulfonate) prepared in this manner from hydrocortisone is foundto melt at 295296 C.

EXAMPLE 2 Preparation of A-17a-hydr0my-3J1,20-triketopregnenyZ-ZI-pyridinium chloride Cortisone(3.6 g.) was reacted with p-toluene sulfonyl chloride (2.4 g.) inpyridine (50 ml.) and allowed to stand in the dark for 12 days.

The solid was collected and washed with acetone to give 4.4 g. of thedesired product, M. P.

284-28? C. The solid was recrystallized from v Preparation of M4 15,1 7a-dihydromy-3z0-diketo- 21 -pyridinium chloride Hydrocortisone (100 mg.)was dissolved in 2 ml. anhydrous pyridine and treated with 65 mg.p-toluenesulfonyl chloride at room temperature for 24.- hours. Thereaction mixture was concentrated to dryness at 60 C. in vacuo and theresidue triturated with 5 ml. acetone. The solid was collected and'airdried to give 56 mg. of product, M. P. 295-300 C. A portion of the solid21-pyridinium chloride derivative of hydrocortisone was recrystallizedfrom methanol-ether.

Calc. for C26H3404NC12 C, 7. H, 7.45. Found: C, 67.37; H, 7.16.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.

Insofar as these changes and 'modifications are '4 within the scope ofthe appended claims, they ar to be considered as part of this invention.

I claim: 1. A -17a-hydroxy-3J1,20-triketopregnenyl-21- 5 pyridiniump-toluenesulfonate having the for- 2. A-116,17;-dihydroxy-3,20-diketopregnenyl- 20 21-pyridiniump-toluenesulfonate having the formula (I) Hr 3. A-17a-hydroxy3,11,20-triketopregnenyl-21- pyridinium chloride having theformula Ha-N C gLl 4. A -11c,17a-dihydroxy-3,20-diketopregnenyl- 521-pyridinium chloride having the formula (KHz-bi (OH I l J [01] l co 1i I V (fH:N

: l R l [X] wherein R is a substituent from the group consisting of ketoand hydroxy, and X is an anion from the group consisting of halides andaromatic sulfonic acid radicals.

6. The process which comprises reacting cortisone with pyridine in thepresence of p-toluenesulfonyl chloride, concentrating the resultingreaction mixture to dryness, triturating the residue so obtained withacetone, recovering the solid product from said acetone slurry, andcrystallizing said solid from a lower aliphatic alcohol to obtain A-17ahydroxy-3,11,20-triketopregnenyL 21-pyridinium p-toluenesulfonate.

7. The process which comprises reacting cortisone with pyridine in thepresence of p-toluenesulfonyl chloride, recovering the solid productfrom the resulting reaction mixture, and washing said solid product withacetone to obtain A -1'7ahydroxy-3,11,20-triketopregnenyl-21 pyridiniumchloride.

8. The process which comprises reacting hydrocortisone with pyridine inthe presence of ptoluenesulfonyl chloride, concentrating the resultingreaction mixture to dryness, triturating the residue so obtained withacetone, and recovering the solid A-11B,17a-dihydroxy-3,20-diketozl-pyridinium chloride from said acetoneslurry.

9. The process which comprises reacting cortisone with pyridine in thepresence of p-toluenesulfonyl chloride to form a mixture of A-17ahydroxy-3,11,20-triketopregnenyl-21 pyridinium chloride and A-17u-hydroxy-3,11,20-triketopregnenyl-zl-pyridinium p-toluenesulfonate.

10. The process which comprises reacting hydrocortisone with pyridine inthe presence of p-toluenesulfonyl chloride to form a mixture of A-11fi,17a-dihydroxy-3,20- diketopregnenyl 21 pyridinium chloride and A-1118,17a-dihydroxy- 3,20-diketopregnenyl-2l-pyridiniump-toluenesulfonate.

11. The process which comprises reacting cortisone with pyridine in thepresence of an aromatic sulfonyl halide to form a mixture of theill-pyridinium halide and the 21-pyridinium aromatic sulfonate,derivatives of cortisone, and separating said halide and aromaticsulfonate salts.

12. The process which comprises reacting hydrocortisone with pyridine inthe presence of p-toluenesulfonyl chloride to form a mixture of A-17e-hydroxy-3J 1,20-triketopregnenyl-21- pyridinium chloride and A-17a-hydroxy-3,11,20- triketopregnenyl-2l-pyridinium p-toluenesulfonate.

13. The process which comprises reacting a compound of the formula:

CHzOH JOHN P. CONBERE.

No references cited.

1. $4-17A-HYDROXY-3,11,20-TRIKETOPREGNENYL-21PYRIDINIUMP-TOLUENESULFONATE HAVING THE FORMULA